Cardiovascular Research

Cardiovascular Research 1999 44(2):242-246; doi:10.1016/S0008-6363(99)00224-2
© 1999 by European Society of Cardiology

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Copyright © 1999, European Society of Cardiology

A plethora of mechanisms in the HERG-related long QT syndrome

Genetics meets electrophysiology

Dan M Roden^a,b,* and Jeffrey R Balser^b,c

^aThe Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA
^bThe Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA
^cThe Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA

^* Corresponding author. Division of Clinical Pharmacology, 532 Medical Research Building I, Vanderbilt University School of Medicine, 23d Ave. South at Pierce Avenue, Nashville, TN 37232-6602, USA. Tel.: +1-615-322-0067; fax: +1-615-343-4522 dan.roden{at}mcmail.vanderbilt.edu

Received 12 July 1999; accepted 12 July 1999

See article by Nakajima et al. [15] (pages 283–293) in this issue.

The ether à-go-go-related gene (eag) was cloned from a Drosophila mutant displaying a dance-like movement disorder on exposure to ether [1]. Homologs of eag have been cloned in mouse and rat, but not (at least yet) in human. However, a related gene, the human ether à-go-go-related gene (HERG) was cloned from a human hippocampal cDNA library in 1994 [2]. The function of HERG was initially obscure, but came to dramatic attention in early 1995 when Keating et al. [3] identified mutations in HERG linked to one form of the congenital long QT syndrome (LQT2), and shortly thereafter HERG was identified as the -subunit encoding the rapid component of delayed rectifier (I_Kr) [4,5]. Thus, HERG rapidly became of interest not only to geneticists interested in LQTS, but also to cardiac physiologists and pharmacologists interested in studying I_Kr and its block by drugs.

Studies from multiple laboratories have now made it clear that the vast majority of drugs associated with Torsades de Pointes are also I_Kr blockers [6–14]. This finding, in turn, can go a long way in explaining the similarities between the congenital and drug-induced forms of the long QT syndrome, and may have important implications for drug development. Quite independent of the long QT syndrome, the availability of a cDNA encoding the structural subunit underlying I_Kr has provided a crucial reagent for biophysicists studying the normal physiology, and the pathophysiology, of the channel. Therefore, mutagenesis of HERG is proceeding along two complementary lines: directed by physiology (often targeting residues or domains known to be important in other voltage-gated channels) or by clinical genetics, as new mutations are identified and characterized in patients with LQT2. The two approaches together are developing an increasingly sophisticated view of the role of individual residues, or specific domains, in modulating I_Kr function (Table 1). In this issue of Cardiovascular Research, Nakajima et al. [15] report the effects of an LQT2 mutation in the 4th transmembrane segment (S4), the putative voltage sensor. The data provide new insights into channel protein behavior, and raise further questions which will doubtless fuel additional biophysical studies.

View this table: [in this window] [in a new window]   Table 1 Reported functional effects of HERG mutationsa

 

	1 HERG mutations cause multiple defects in IKr

Top 1 HERG mutations cause... 2 An LQT2 mutation... 3 How many mutations,... References

 
Outward current through HERG channels to generate I_Kr is assumed to promote repolarization. Indeed, one of the most intriguing aspects of I_Kr physiology (actually described before HERG was cloned) is the very rapid and extensive inactivation that the current undergoes during depolarizing pulses [16]. This effect makes I_Kr an especially important player in normal repolarization, since the current increases so dramatically (further hastening repolarization) as membrane potential recovers to more negative values and channels are thereby moved from inactivated to open states [17,18]. When mutations in HERG were identified in patients with the long QT syndrome, and HERG was found to underlie I_Kr, the natural assumption was made that the mutations would result in decreased I_Kr, and hence prolonged QT intervals. While studies of individual mutations have borne out this natural prediction, what has been a very interesting evolving story is that multiple mechanisms now appear to be involved. As shown in Table 1, some mutant channels can generate I_Kr in heterologous expression systems, but the current displays altered gating or reduced amplitude. Expression of other mutant channels produces no I_Kr, and two distinct mechanisms have been reported: in some cases, channel protein cannot be detected at the cell surface, suggesting that the lack of function reflects a problem with trafficking or stability of the protein [19–21], while in other cases, channel protein is detected at the cell surface, suggesting a primary defect in gating [19].

There does not seem to be a simple correlation between the location or nature of the mutation, and the functional consequences: for example, two pore mutations, I593R and G628S, are detectable at the channel surface, but result in no functional channels while a third, Y611H, decreases I_Kr function as least in part through a defect in processing, since the channel protein is retained in the endoplasmic reticulum [19]. A similar effect was observed with V822M, a C-terminal mutation. Studies of C-terminal splice variants have also implicated a domain in this region as important in trafficking, although the exact mechanism remains to be determined [22]. While LQT2 mutations resulting in single amino acid substitutions have been described in most domains of the channel (Table 1), one exception to date has been the S4–S5 linker. Sanguinetti and Xu [23] have presented evidence that this region is a crucial component of the HERG activation gate. It is tempting to infer that mutations in such an important region might introduce such severe functional changes as to not be compatible with life.

In order to study further the functional consequences of LQT2 mutants, a common approach is co-expression of wild-type and mutant cDNAs, in analogy to what is presumed to occur in a patient with a single wild-type and mutant allele. In some cases, the functional effect on I_Kr is simply additive, implying no interaction between mutant and wild-type proteins [21,24]. In others, co-expression results in changes in function or current amplitude that are most likely attributable to a direct interaction of mutant and wild-type proteins, often with a ‘dominant negative’ functional result [22,24,25]. Interestingly, subtle mutations, such as a single nucleotide change, may give rise to profound dominant negative I_Kr suppression, whereas more extensive deletions may actually produce a less severe functional defect because of lack of a dominant negative effect [24]. Since both the C-terminus and N-terminus of HERG include splice variants, and co-expression of the splice variants with the canonical channel results in altered channel gating and/or current amplitude [22,26,27], the possible outcomes of coexpression of multiple mutant and wild-type channels seems large.

	2 An LQT2 mutation in the voltage sensor

Top 1 HERG mutations cause... 2 An LQT2 mutation... 3 How many mutations,... References

 
In this issue of Cardiovascular Research, the Hiraoka laboratory reports the electrophysiologic effects of R534C, a charge neutralizing LQT2 mutation in S4 [15]. In this and most other voltage-gated potassium, sodium, and calcium channels, S4 includes a positive residue (arginine [R] or lysine [K]) at every 3rd position, and is thought to act as a voltage sensor, moving outward during depolarization and thus initiating conformational changes that culminate in depolarization-induced currents. R534C mutations expressed in Xenopus oocytes did display I_Kr, although activating current was much reduced compared to wild-type. However, the R534C mutation resulted in a prominent negative shift in the voltage-dependence of channel activation. This is an unanticipated result, since loss of a positive charge would be predicted to shift the voltage-dependence of activation in the positive direction (i.e. require a greater change in the membrane potential to activate the channel).

A solution to this apparent paradox may be manifest in detailed biophysical studies over the last 2 years concerning the role of S4 in Shaker K⁺ channel activation. Shaker, like HERG, is a tetrameric structure, with each of the four subunits containing an S4 segment, which may interact cooperatively during gating processes. A consensus view presented recently [28] suggests that the activation (channel opening) process consists of a series of sequential steps. In the first stage, each of the four S4 segments moves essentially independently as the positive charges are pulled outwardly through the membrane field. In the second stage, after this initial ‘unlatching’ process, the four S4 subunits act cooperatively to open the pore and allow K⁺ permeation. Although the structural details of this second cooperative step remain mysterious, it is possible that not all of the S4 positive charges facilitate this step, and may in some ways impede the final stages of opening. If this model applies to HERG activation, the 534 arginine might reside in a locus (within the three-dimensional structure) that minimally influences the initial voltage-dependent outward motion of S4, but does importantly resist the subsequent cooperative process of channel opening. In this scenario, charge substitution (e.g. R534C) could shift the activation voltage-dependence in a negative direction, and speed the rate of activation, as observed by Nakajima et al. [15].

Indeed they report not only the negative shift in voltage dependence of activation but also accelerated activation and deactivation, and reduced steady state inactivation. The authors postulate that by influencing the movement of S4, a conformational change is induced in both the activation gate (?S4–S5 [23]) and some domain, possibly extracellular, involved in inactivation. Co-expression of R534C with wild-type channels showed no evidence of a dominant negative or other mutant/wild-type interaction. Most intriguingly, action potential simulations incorporating R534C changes in activation and inactivation kinetics and voltage dependence actually shortened action potential duration slightly. Thus, the changes in gating, while interesting and perhaps providing insight into channel protein function, do not explain the QT prolongation (which was quite severe) in the R534C family. It may well be that the major effect is to decrease the number of channels present in the cell membrane. The striking reduction in activating current is consistent with this idea, and studies of membrane protein trafficking in mammalian cells will be required to sort this out.

What is unexpected is that a charge-neutralizing point mutation in the putative voltage sensor does not result in the predicted straightforward positive shift in the voltage dependence of activation, but rather a complex set of changes in both activation and inactivation. This result, in turn, further reinforces the concept that the conformational changes that these membrane proteins undergo in response to a change in electric field are far from totally unraveled. One important step in approaching this problem would be a clear idea of the three-dimensional structure of the protein; a crystal structure has recently been proposed for the N-terminal domain, and a regulatory function for this region inferred [29]. There are other outstanding questions with regard to this intriguing protein, such as how LQT2 (or other QT prolonging) mutations actually generate arrhythmias [30]; the connection – or lack thereof [31] – between defects in channel function identified in vitro and the clinical phenotype; the role of MiRP1, a recently-described I_Kr-modulating ancillary protein subunit [32]; and the possible function of HERG expression in extracardiac physiology and pathology [33–35].

	3 How many mutations, in how many genes?

Top 1 HERG mutations cause... 2 An LQT2 mutation... 3 How many mutations,... References

 
Modern genetic techniques have been, and continue to be, key in identifying reagents such as HERG, and pointing to specific loci on these molecules at which function-altering mutations arise. The challenge to modern molecular electrophysiology is to use these clues to further interpret normal channel function. Ultimately, improved understanding of altered channel function in disease, and hence treatment, should emerge. It has been pointed out that there is a coming ‘data flood’ in many areas of science, clinical genomics among them [36]. It seems highly likely that the next several years will see identification of a huge number of new ‘reagents’ like HERG, and a correspondingly enormous number of mutations and polymorphisms in the human genome that may be associated with disease or response of disease to specific therapies. To date, at least three dozen missense mutations have been reported in LQT2, along with about a dozen mutations truncating the protein at various sites, but only a minority have been fully characterized. Thus, while human genetics provides much new data to drive interesting and insightful physiologic studies, it seems to us that this data flood presents at least two important challenges. The first will be in deciding to which genes, and to which mutations, resources and investigator effort should be applied. And the second is determining how detailed dissection of mechanisms, such as those presented here, can be integrated into a global understanding of channel function, action potential control, and response of the heart and the organism to exogenous stressors.

	Acknowledgements

 
Supported by grants from the USPHS (HL 49989, HL 46881). Dr Balser hold the James Taloe Gwathmey Clinician Scientist Chair, and is an Established Investigator of the American Heart Association. Dr Roden is the holder of the William Stokes Chair in Experimental Therapeutics, a gift of the Daiichi Corporation.

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